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BioOncology Watch Timely Information for Practicing
Physicians |
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DECEMBER 1999 Non-Hodgkin’s Lymphoma
(NHL) Vaccine-induced molecular remission. Clonal B-cell cancers, such as follicular
lymphoma (FL), express unique immunoglobulin (Ig) idiotypes that can serve as
tumor-associated antigens. Maurizio
Bendandi and coworkers isolated Ig protein from FL patient tumors and
conjugated the patient-specific Ig to keyhole limpet hemocyanin (KLH) for
optional cytotoxic T-lymphocyte (CTL) activation. The Ig-KLH complex was mixed with GM-CSF as an adjuvant for
enhanced induction of immune effector cells and administered as 4 monthly
subcutaneous vaccinations. 20 FL
patients with chemotherapy-induced CRs were vaccinated in this manner after ³ 6
months of immune recovery following chemotherapy. Post-vaccination, tumor specific CTLs were found in 19 of 20
patients, and vaccination was associated with clearance of residual tumor
cells from the blood of 8 of 11 patients with the t (14; 18) abnormality (PCR
analysis). 18 patients remain in CR
with a median duration of 42+ months (range 28+ to 53+ months). These results show that an anti-tumor
effect is achievable with lymphoma-specific vaccination and justify further
studies in the minimal residual disease setting. (Bendandi M, et al. Nature
Medicine 1999; 5: 1171-1177) Negative adjuvant therapy trial with
anti-B4-blocked ricin (Anti-B4-bR) immunotoxin. Anti-B4-bR (Immuno Gen, Inc.) is an
immunotoxin that combines an anti-B4 (CD19) antibody with the cytotoxicity of
a blocked-ricin toxin. Michael
Grossbard et al. conducted a phase II study in which 49 B-cell NHL patients
in complete remission following myeloablative chemotherapy and autologous
bone marrow transplantation (ABMT) received anti-B4-bR 30ug/kg daily x7 by
continuous i.v. infusion every 14 days for up to 3 courses. Although human antimouse antibody (HAMA)
and/or human antiricin antibody (HARA) responses developed in 23 patients,
the immunotoxin was well tolerated with reversible toxicities. While this trial experience demonstrated
that an immunotoxin can be given safely to post-ABMT patients, the 4-year
results showed continued relapse, moreover, a phase III Intergroup trial was
stopped due to lack of efficacy.
Other immunotherapies are being studied in the adjuvant setting (e.g.,
Rituxan®). (Grossbard ML, et al. Clin Cancer Res 1999; 5: 2392-2398) Colon Cancer
Responses to an anti-idiotype monoclonal antibody. The carcinoembryonic antigen (CEA) is an
excellent target for immunotherapy due to its presence in high titers on the
tumor cell surface. However, CEA is
seen as a self-antigen by the immune system. To overcome immune tolerance to
CEA, Kenneth Foon and associates generated and studied an anti-idiotypic
monoclonal antibody (CeaVac; Titan Pharmaceuticals, Inc. and Aquila
Biopharmaceuticals) capable of inducing a specific anti-CEA immune response
by a host. 32 patients with resected
Dukes’ B, C, and D and partially resected Dukes’ D disease were treated with
CeaVac (2mg i.v.) every other week x
4 and than monthly until progression or tumor recurrence (14 patients were
also receiving 5-FU chemotherapy).
All 32 patients (including the 5-FU-treated patients) developed high
titer IgG and T-cell proliferative responses against CEA. Several patients have done well clinically
and remain in the study. These
results demonstrate that immune tolerance to CEA is circumvented by CeaVAc,
that 5-FU chemotherapy does not affect immune response, and that phase III
trials to confirm clinical efficacy are warranted. (Foon KA, et al. J.
Clin Oncol 1999; 17: 2889-2895) Renal Cell Carcinoma (RCC) Identification of a potential immunotherapy target.
Recently the G250 antigen has been sequenced and found to be
homologous with a tumor-associated antigen (MN/CA IX antigen) identified in
He La cells. Utilizing a monoclonal
antibody to the G250 antigen and RT-PCR analysis to detect G250 antigen mRNA
expression, Uemura and colleagues studied 147 cases of RCC. While a lack of expression was observed in
normal tissues, the G250 antigen was detected in 128/147 RCC samples (87%)
and G250 antigen mRNA was found in 137/147 RCC samples (93%). High grade and advanced stage tumors had a
lower expression of this antigen.
These findings indicate that the G250 antigen is a potential immunotherapeutic
target, as well as a diagnostic marker for RCC. (Uemura H, et al. Brit
J Cancer 1999; 81: 741-746) Interleukin 2 (IL-2) Direct gene transfer. Compared to the systemic administration of
IL-2, IL-2 gene therapy has been shown in animal models to increase efficacy
without the associated systemic toxicity.
Galanis and coworkers completed a phase I study (n=24) and 3 phase
I/II studies (n=52) of a gene transfer product containing a plasmid encoding
human IL-2 formulated with a cationic lipid complex (Leuvectin; Vical Inc.)
administered via intratumoral injection.
Mild constitutional symptoms developed in most patients with only one
grade 3 toxicity (rigors) and no drug-related grade 4 toxicities
reported. The plasmid was detected in
post-treatment samples of 29 of 46 patients tested by PCR assay. Partial responses were achieved in 3
patients (2 with renal cell ca and 1 with melanoma) and stable disease has
been observed in another 11 patients.
Intratumor injection of Leuvectin is safe and represents a potentially
effective immunotherapeutic modality.
(Galanis E, et al. J Clin
Oncol 1999; 17: 3313-3323) Cervical Cancer
Human
leukocyte antigen (HLA) class I gene mutations. Cellular immune function that detects and
destroys malignant cells requires normal HLA class I expression. Louise Koopman et al. used PCR-based
techniques to determine if gene mutations cause the loss of allele-specific
HLA class I expression in cervical carcinomas. They studied two cervical carcinoma cell lines and tissue
samples from the tumors from which these cell lines were derived. In bothcell lines nucleotide changes were
found in exons encoding extracellular domains, in the HLA-B15 gene in one
tumor and in the HLA-A24 gene in the other tumor, which resulted in stop
codons that block the expression of functional proteins. These data provide evidence that gene
mutations cause the loss of HLA class I expression and represent a mechanism
by which tumors do not succumb to cytotoxic T-lymphocytes. (Koopman LA, et al. J Natl Cancer Inst 1999; 91:
1669-1677) |
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